Abstract
Targeted protein degradation (TPD) technology has drawn significant attention from researchers in both academia and industry. It is rapidly evolved as a new therapeutic modality and also a useful chemical tool in selectively depleting various protein targets. As most efforts focus on cytosolic proteins using PROteolysis TArgeting Chimera (PROTAC), LYsosome TArgeting Chimera (LYTAC) recently emerged as a promising technology to deliver extracellular protein targets to lysosome for degradation through the cation-independent mannose-6-phosphate receptor (CI-M6PR). In this study, we exploited the potential of the asialoglycoprotein receptor (ASGPR), a lysosomal targeting receptor specifically expressed on liver cells, for the degradation of extracellular proteins including membrane proteins. The ligand of ASGPR, triantennary N-acetylgalactosamine (tri-GalNAc), was conjugated to biotin, antibodies, or fragments of antibodies to generate a new class of degraders. We demonstrated that the extracellular protein targets could be successfully internalized and delivered into lysosome for degradation in liver cell lines specifically by these degraders. This work will add a new dimension to TPD with cell type specificity.
Highlights
IntroductionMost proteins in eukaryotic cells are degraded through ubiquitin-proteasome system, where the E3 ubiquitin ligase recognizes a specific protein substrate and tags multiple ubiquitin motifs to it, leading to the subsequent proteolysis by the proteasome[1, 2]
Protein degradation is essential for maintaining cellular protein homeostasis
As most efforts focus on cytosolic proteins using PROteolysis TArgeting Chimera (PROTAC), LYsosome TArgeting Chimera (LYTAC) recently emerged as a promising technology to deliver extracellular protein targets to lysosome for degradation through cationindependent mannose-6-phosphate receptor (CI-M6PR)
Summary
Most proteins in eukaryotic cells are degraded through ubiquitin-proteasome system, where the E3 ubiquitin ligase recognizes a specific protein substrate and tags multiple ubiquitin motifs to it, leading to the subsequent proteolysis by the proteasome[1, 2]. Both intracellular and extracellular proteins enclosed in vesicles can be delivered into lysosomes for degradation[3, 4] Based on these mechanisms, targeted protein degradation by chimeric molecules emerged as a novel therapeutic modality. CIM6PR has been used to deliver therapeutic drugs conjugated with mannose-6-phosphate (M6P) derivatives for lysosomal enzyme replacement therapy and cancer treatment[9, 10] Various molecules, such as peptides, proteins or liposome, were covalently linked to the modified M6P with enhanced affinity and stability to achieve targeted drug delivery[11,12,13,14]. It has been shown that LYTAC could successfully degrade both secreted and membrane proteins in the lysosome through CI-M6PR.[8]
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